The focus of this proposal is the development of polyoxometalate-based agents to inhibit HIV-1, the causative agent in AIDS. There are 3 main specific aims in this program. First, methods for the synthesis, purification and characterization of key polyoxometalate drugs including two top candidates, Si2W18Nb6O778- (1) and (Fe)4(H2O)2(P2W15O56)216- (2) and polyoxometalates with covalently attached organic groups will be further developed. Compound 1 exhibits high activity against HIV-1 and no detectable toxicity in a variety of cell cultures and appears to be well tolerated in mammals. Compound 2, while less developed thus far than 1, looks equally promising. The attachment of organic groups to polyoxometalates may lead to hydrophobic complexes with higher levels of blood-brain barrier permeability, higher degrees of oral bioavailability (and in particular optimized g.i. transport), and even higher mammalian tolerance. Second, newly discovered anti-HIV active and nontoxic polyoxometalates that are also potent and selective inhibitors of HIV- protease will be further studied. The detailed binding domain and mechanism of action will be probed. Large polyoxometalates including 1 and 2 that can prevent viral entry and the binding/fusion of uninfected and HIV-infected lymphocytes will be further investigated. Assays have been developed that should provide an insight into the mechanism of binding/fusion of certain polyoxometalates. Third, the mechanism of action of 1 and 2 and other lead compounds will be probed by in vitro selection of polyoxometalate-resistant strains. These studies will provide a rationale for studying drug combinations that may be clinically useful.